Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1'-O-isopropyl ether Shows Improved Selectivity Against the Epstein-Barr Virus Lytic Cycle

Máté Vágvölgyi, Gábor Girst, Norbert Kúsz, Sándor B. Ötvös, Ferenc Fülöp, Judit Hohmann, Jean Yves Servais, Carole Seguin-Devaux, Fang Rong Chang, Michael S. Chen, Li Kwan Chang, Attila Hunyadi

Research output: Contribution to journalArticle

Abstract

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4'-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1'-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.

Original languageEnglish
JournalInternational journal of molecular sciences
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 12 2019

    Fingerprint

Keywords

  • antitumor
  • antiviral
  • continuous-flow chemistry
  • drug discovery
  • Epstein–Barr virus
  • lytic cycle
  • natural product
  • oxime
  • protoflavonoid

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this